The present invention relates to novel tri-iodinated 5-aminoisophthalic acid derivatives.
In the field of X-ray diagnostics, for example, for visualization of the urine-excreting organs and the vessels to be detected angiographically, well compatible salts of 2,4,6-triiodobenzoic acids have been developed as the contrast media. These substances, however, are not tolerated by the host organisms without side effects at higher dosages, although their toxicity is frequently low. Adequate representation of the vascular system, the urinary tract, and also the cerebrospinal cavities and other systems, requires the use of high dosages of contrast medium or of highly concentrated solutions. Thus, the physicochemical properties of the contrast media and their solutions are of particular importance since essential pharmacological effects, such as pain, drop in blood pressure, vascular damage, and many others are attributed to these properties.
With the development of dimers of such compounds, obtained by linking together two triiodinated benzoic benzoic acids, it has been possible, inter alia, to improve neural compatibility and reduce vasodilation in angiography as compared to the monomeric triiodinated benzoic acids. Due to the somewhat lower osmotic pressure associated with such dimers, for example, of the dimeric iocarmic acid (as the dimeglumine salt), the concentration in the urine is increased.
With the introduction of the nonionic metrizamide, it has been possible for the first time to significantly lower the osmotic pressure in a monomeric, triiodinated contrast medium. Also in metrizamide, the osmotic pressure of a solution, suitable for example for angiography (300 mg iodine/ml) is, at 12 atmospheres, still considerably above the osmotic pressure of the blood (7.5 atmospheres). Its suitability for myoelography, angiography and urography has been described in several articles in Acta Radiol. Suppl. 335 (1973).
However, all heretofore described water-soluble contrast media, just as metrizamide, are useless for lymphography in which the physical properties of the X-ray contrast medium also play an important role. In medical practice, iodinated oils, e.g., iodinated fatty acid esters of poppy oil are presently used predominantly for lymphography. These agents, on the one hand, show a good storage capability in the lymph nodes and a good contrast effect, but, on the other hand, cannot be used generally nor without problems due to their known side effects. In view of the fact that lymphatic vessels can be injured readily, especially in the case of too rapid an administration, these media can promote lesions of the lymphatic vessels. A number of disadvantages are due to the oily character of these contrast media: since suspension of the oil takes place only in the blood, the size of the oil droplets cannot be predetermined. If the oil droplets are too large, oil microembolisms, for example, in the lungs, are frequently unavoidable. Since the absorption of the large oil droplets into the interstitial cavities in the lymphatic capillaries is hardly possible, a visualization of the lymphatic channels and lymph nodes, for example, after subcutaneous or intraparenchymatous injection, is accomplished only in rare cases.
The latter disadvantage can only be overcome by endolymphatic application, but in this case it is necessary to first mark the medium with a dye, which likewise is not without complications, and an operative uncovering of the lymphatic vessels under local anesthesia must be carried out. Finally, the contrast media based on these iodinated oils are excreted only very gradually after application. Depending on the form of preparation, the excretion period can be weeks to months.
Attempts have been made to overcome the above-described disadvantages by an emulsification of these iodinated oils. Although the viscosity and the droplet size have thus been reduced, whereby the capillary passage could be improved and, if the emulsion was stable, the risk of embolism formation could be lowered, such partial success has been at the cost of incurring other disadvantages. Examples which may be mentioned in this connection are: an effective reduction of the iodine content per milliliter of contrast medium and a concomitant, unavoidable loss in contrast; a higher local toxicity on lymph nodes; hepatotoxic effects; and a histologically detectable foreign-body reaction, aggravated by the added emulsifiers.
All contrast media based on iodinated oils possess low stability and can be used only to a limited extent because of the above-described side effects.
The conventional, water-soluble, organic iodine compounds used in the conventional preparations for uro- and angiography have also proved to have little or no suitability for lymphography, because they diffuse too quickly out of the lymphatic vessel system after application. Due to this lack of storage capability in the lymph nodes, these aqueous forms of preparations are suitable, within limits at best, for peripheral lymphangiography.
Also, experiments with crystalline suspensions based on nuclear-iodinated aromatics, such as, for example, iodamide or tetraiodoterephthalic acid derivatives, have failed to produce contrast media for lymphography useful in medical practice. Such media possess insufficient compatibility (inflammation manifestations at the injection site and in the lymphatic system) and excessively long excretion periods (days to weeks).
In summation, it can be seen that lymphograhy with these conventional X-ray contrast media is impossible without involving risk. It, thus, can be conducted only on an in-patient basis. Further, the patient must be tested very carefully for his/her suitability for this examination. At least three days are required for conducting such an examination, including the suitability test and the actual lymphography.